Efficacy and safety of bintrafusp alfa in two phase 1 expansion cohorts with advanced hepatocellular carcinoma

Background and Aims Simultaneous inhibition of the TGF-β and PD-L1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1, was evaluated in patients with advanced HCC. Approach and Results In this global, open-label, phase 1 study (NCT02517398), patients with PD-L1–unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200 mg every 2 weeks in a dose-escalation (n=38) or dose-expansion (n=68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. Primary endpoint was best overall response (BOR) per Response Evaluation Criteria in Solid Tumors 1.1 by independent review committee. Secondary endpoints included investigator-assessed BOR, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8-44.2) and 38.6 (33.5-39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate (ORR) was below the prespecified 20% ORR threshold set to evaluate efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients). Conclusions Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.